US4778792A - Use of 7-acyl benzoxazinones and their derivatives in treating atheromatous disorders - Google Patents

Use of 7-acyl benzoxazinones and their derivatives in treating atheromatous disorders Download PDF

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Publication number
US4778792A
US4778792A US06/921,561 US92156186A US4778792A US 4778792 A US4778792 A US 4778792A US 92156186 A US92156186 A US 92156186A US 4778792 A US4778792 A US 4778792A
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United States
Prior art keywords
group
carbon atoms
benzoxazinone
divalent
heterocyclic group
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Expired - Fee Related
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US06/921,561
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English (en)
Inventor
Isabelle Lesieur
Charles Lespagnol
Ziaddine Moussavi
Jean-Claude Fruchart
Jacques Sauzieres
Nicole Monfilliette
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Laboratories Negma SA
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Laboratories Negma SA
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Assigned to LABORATOIRES NEGMA reassignment LABORATOIRES NEGMA ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: FRUCHART, JEAN-CLAUDE, LESIEUR, ISABELLE, LESPAGNOL, CHARLES, MONFILLIETTE, NICOLE, MOUSSAVI, ZIADDINE, SAUZIERES, JACQUES
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • the invention relates to 7-acyl benzoxazinones (or 7-acyl (2H)-1,4-benzoxazine-3 (4H) ones) and derivatives of the latter, and a process for obtaining them.
  • the products of the invention are devoid of toxicity and show a wide range of pharmacological properties enabling their use in various therapeutic fields.
  • the invention therefore relates also to pharmaceutical compositions containing these products in association with a pharmaceutically acceptable vehicle.
  • R 1 is either hydrogen group comprising from 1 to 6 carbon atoms, preferably alkyl, alkaryl or aralkyl, as the case may require, carrying substituents, particularly of the type envisaged below with respect to the group X, or a heterocyclic group, particularly thienyl, furyl, pyridinyl or pyridyl,
  • R 2 and R 3 are each, and this independently from one another, hydrogen or an alkyl group comprising from 1 to 6 carbon atoms,
  • R is a hydrogen group formed from cyclic or aliphatic elements, or both at once, comprising from 1 to 15 carbon atoms, or one of the above-said heterocyclic groups,
  • X is hydrogen or a carboxyl, halogen, hydroxyl, nitro, amino, itself substituted or not by one or two alkyl groups containing from 1 to 4 carbon atoms or a heterocyclic amino group, alkoxyl comprising from 1 to 4 carbon atoms, X being also capable of defining a chemical ring-forming bond formed between R and the carbon atom at the 6 position of the benzene ring of the benzoxazinone part of the molecule, as well as, if there is occasion, the corresponding salts or esters, and the optical isomers when R 2 and R 3 are different.
  • R 1 , R 2 , and R 3 are, independently of one another, hydrogens or methyl groups.
  • R is an aryl group particularly phenyl, arylalkyl or heterocyclic, alkaryl particularly benzyl, alkyl including here cyclopropyl, comprising from 1 to 6 carbon atoms or one of the above-said heterocyclic groups,
  • X being a hydrogen or a halogen, particularly chlorine or bromine, a hydroxyl or an amino group, particularly piperazine, substituted or not, or again one of the above-said heterocyclic groups.
  • a second prefered class of compounds according to the invention is formed from alpha-beta ethylenic ketones in which the group R is an aliphatic chain of which the first carbon, at the alpha position of the carboxyl group is the carrier of an ethylenic branch group, particularly methylene.
  • the group CO--R is then a 2-methylene butyryl group.
  • the group R is a --C ⁇ --X--X group, in which W is an alkyl, arylalkyl or aryl group, particularly --C ⁇ C--C 6 H 5 --X, X being hydrogen or a halogen, an amino group or hydroxyl, methoxyl or nitro.
  • R is an aliphatic chain comprising 2 or 3 carbon atoms, possibly branched by an R 4 group (preferably alkyl) comprising from 1 to 4 carbon atoms, and forming a ring-closing bond of this chain with the carbon atom at the 6 position on the benzene ring of the benzoxazinone group.
  • the 5-acyl 2-amino phenols, in which R 1 is hydrogen have been obtained by hydrolysis of corresponding 6-acyl benzoxazolinones and under the conditions described in the patent.
  • R 1 is, for example, a methyl group
  • the following operational method is employed:
  • a preferred process of the invention to obtain the "compound of group I" comprises a condensation reaction between a derivative of the corresponding aminophenol of the formula: ##STR5## in which R 1 , R and X have the above-indicated meanings and Z is hydrogen (the reaction being then preferably conducted in an alkaline medium) an alkali metal, particularly sodium, and an alphahalogenic ester of the formula: ##STR6## in which R 2 and R 3 have the above-indicated meanings, Y is halogen, particularly bromine, and R 4 an alkyl group, particularly methyl or ethyl, or alkaryl, aralkyl or aryl.
  • a preferred process for obtaining the compounds of group II is obtained by subjecting the compounds of group I in which R--X form an alkyl or arylalkyl group, for example n-propyl, to a reaction in the presence of formaldehyde and amine in an acetic acid medium or in the presence of a reagent such as N'N'N'N'-tetramethyl diamino-methane in the same medium.
  • a preferred process consists, starting from a “compound of the first group", of treating it in an organic solvent with the aldehyde X--W--CHO, in which X and W have the above-indicated meanings, in particular benzoic aldehyde.
  • R is an aliphatic hydrocarbon group containing at least 3 carbon atoms preferably at least 4.
  • the raw materials of these derivatives are 2-amino 5-acyl phenols.
  • Recrystallization solvent acetone or acetonitrile
  • Recrystallization solvent 95° alcohol or ethyl acetate
  • Recrystallization solvent acetone or absolute alcohol or 95° alcohol
  • Recrystallization solvent absolute alcohol or 95° alcohol
  • Recrystallization solvent absolute alcohol or methanol
  • Recrystallization solvent cyclohexane or absolute alcohol
  • Recrystallization solvent hexane or cyclohexane
  • Recrystallization solvent hexane or absolute alcohol
  • the 5-acyl 2-amino phenol MZ 83 of the formula: ##STR44## from 6-(4-bromo butyryl)3-methyl benzoxazolinone by treating it in a strong basic medium, more particularly with a 20% sodium hydroxide solution. It is heated for one hour at 80° C. then this solution is cooled and it is neutralized with a dilute hydrochloric acid solution (pH 6.5-7). In this manner opening of the benzoxazolinonic ring and dehalohydrogenation at the alpha position of its ketone group have been effected therefore simultaneously.
  • the chemical characteristics of the product MZ 83 are as follows:
  • Recrystallization solvent half-diluted alcohol
  • Recrystallization solvent cyclohexane or 95° alcohol
  • Recrystallization solvent absolute alcohol or isopropanol or propanol
  • Recrystallization solvent hexane or absolute alcohol
  • the toxicity of the compounds has been determined by the oral route, in the rat.
  • All the compounds have an LD 50 higher than 2000 mg/kg.
  • hyperlipemia hypercholesterolemia, unbalance of the apoprotein ratio A 1 /B or of the LDL Cholesterol/HDL Cholesterol ratio (with LDL: low density lipoproteins and HDL: high density lipoproteins) these lipoproteins being separated by density gradients.
  • LDL low density lipoproteins
  • HDL high density lipoproteins
  • hypolipemic agents are now available: clofibrate, cholestyramine, gemfibrozil, probucol . . . .
  • the products of this invention are original and possess interesting pharmacological properties.
  • Platelet antiagregating activity according to conventional tests (in vitro, on human blood).
  • the normolipemic activity has also been established in OF normal mice or rendered hypercholesterolemic.
  • the products tested were administered per os daily for 15 days at the dose of 50 mg/kg.
  • the change in weight was observed in the course of the treatment, a lipid balance was effected at the end of the experimentation with respect to a control group.
  • HDLs constitute the "purifying fraction" of cholesterol. HDLs transport the cholesterol to convert it at the level of the liver into biliary salts which are eliminated by the bile.
  • compositions according to the invention relate more particularly to pharmaceutical compositions employing the compounds according to the invention in association with a pharmaceutically acceptable vehicle.
  • the compositions according to the invention are in an administrable form, preferably oral, and particularly in solid form.
  • the compounds according to the invention are useful for the treatment of atheromatous disorders involving particularly lipids or glycerides.
  • compositions according to the invention are characterised by an analgesic, anti-inflammatory, sedative, antibacterial, antifungal, cardiovascular activity and an activity on the central nervous system.
  • the total absence of toxicity confers them a particularly favorable therapeutical index.
  • compositions are advantageously prepared in order to allow the administration of unit doses of 1 to 500 mg, when considering more particularly the oral route. Ranges of daily doses useful for the adult can be etablisched between 5 and 1000 mg by day.
  • the invention relates also to the use of the above mentioned components for manufacturing medicaments intended for treatment of cardio-vascular disorders, involving in particular lipids or glucids, or intended for use as analgesic, anti-inflammatory or antifungal components.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Communicable Diseases (AREA)
  • Obesity (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US06/921,561 1985-10-21 1986-10-20 Use of 7-acyl benzoxazinones and their derivatives in treating atheromatous disorders Expired - Fee Related US4778792A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8515595A FR2588868B1 (fr) 1985-10-21 1985-10-21 Acyl-7 benzoxazinones et leurs derives, procede pour les obtenir et compositions pharmaceutiques les contenant
FR8515595 1985-10-21

Publications (1)

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US4778792A true US4778792A (en) 1988-10-18

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US (1) US4778792A (da)
EP (1) EP0223674A1 (da)
JP (1) JPS62126180A (da)
DK (1) DK504986A (da)
FR (1) FR2588868B1 (da)
PT (1) PT83593B (da)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4994104A (en) * 1988-12-19 1991-02-19 Fmc Corporation Tetrahydrophthalimide carbamate herbicidal compositions
US5081242A (en) * 1986-12-22 1992-01-14 Ortho Pharmaceutical Corporation 6-benzoxazinyl- and 6-benzothiazinyl 2,3,4,5-tetrahydropyridazin-3-ones
AU631743B2 (en) * 1990-06-22 1992-12-03 Adir Et Compagnie New chalcones, process for preparing these and pharmaceutical compositions containing them
AU633666B2 (en) * 1986-12-22 1993-02-04 Ortho Pharmaceutical Corporation Benzoxazinyl and benzothiazinyl derivatives
US5185333A (en) * 1989-07-03 1993-02-09 Yoshitomi Pharmaceutical Industries, Ltd. Benzazine compounds and pharmaceutical uses thereof
US20050250772A1 (en) * 2000-04-13 2005-11-10 Shelby Nancy J Methods for inducing anti-anxiety and calming effects in animals and humans
US20060166981A1 (en) * 2000-04-13 2006-07-27 Rosenfeld Mark J Novel compounds for use in weight loss and appetite suppression in humans
US7507731B2 (en) 2003-11-20 2009-03-24 Seroctin Research & Technology, Inc. Compounds for use in weight loss and appetite suppression in humans
RU2788047C1 (ru) * 2021-12-30 2023-01-16 федеральное государственное автономное образовательное учреждение высшего образования "Пермский национальный исследовательский политехнический университет" Седативное средство на основе 3-(2-(4-фторофенил)-2-оксоэтилиден)-3,4-дигидро-2н-бензо[b][1,4]оксазин-2-она

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5268381A (en) * 1990-09-26 1993-12-07 Adir Et Compagnie Aminoalkyl-benzothiazolinone and -benzoxazolinone compounds having a high 5-HT1A affinity
FR2667068B1 (fr) * 1990-09-26 1994-09-09 Adir Nouvelles amines alkyl heterocycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
US5696117A (en) * 1995-11-07 1997-12-09 Ortho Pharmaceutical Corporation Benzoxazine antimicrobial agents
US5707990A (en) * 1996-01-30 1998-01-13 Ortho Pharmaceutical Corporation 2-substituted amino and thio alkyl benzoxazine antimicrobial agents

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1560628A (da) * 1968-02-09 1969-03-21
US3770734A (en) * 1969-02-06 1973-11-06 Bellon R Lab 3-oxo-2,3-dihydro-1,4-benzoxazine derivatives
DE2509155A1 (de) * 1975-03-03 1976-09-09 Hoechst Ag 1,4-benzoxazinderivate und verfahren zu ihrer herstellung
US4358455A (en) * 1980-12-23 1982-11-09 Merck & Co., Inc. Aralkylamindethanol heterocyclic compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1560628A (da) * 1968-02-09 1969-03-21
US3770734A (en) * 1969-02-06 1973-11-06 Bellon R Lab 3-oxo-2,3-dihydro-1,4-benzoxazine derivatives
DE2509155A1 (de) * 1975-03-03 1976-09-09 Hoechst Ag 1,4-benzoxazinderivate und verfahren zu ihrer herstellung
US4358455A (en) * 1980-12-23 1982-11-09 Merck & Co., Inc. Aralkylamindethanol heterocyclic compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Baker, The Journal of Organic Chemistry, vol. 48, No. 25, (1983), pp. 5140 5143. *
Baker, The Journal of Organic Chemistry, vol. 48, No. 25, (1983), pp. 5140-5143.

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5081242A (en) * 1986-12-22 1992-01-14 Ortho Pharmaceutical Corporation 6-benzoxazinyl- and 6-benzothiazinyl 2,3,4,5-tetrahydropyridazin-3-ones
AU633666B2 (en) * 1986-12-22 1993-02-04 Ortho Pharmaceutical Corporation Benzoxazinyl and benzothiazinyl derivatives
US4994104A (en) * 1988-12-19 1991-02-19 Fmc Corporation Tetrahydrophthalimide carbamate herbicidal compositions
US5185333A (en) * 1989-07-03 1993-02-09 Yoshitomi Pharmaceutical Industries, Ltd. Benzazine compounds and pharmaceutical uses thereof
AU631743B2 (en) * 1990-06-22 1992-12-03 Adir Et Compagnie New chalcones, process for preparing these and pharmaceutical compositions containing them
US5179091A (en) * 1990-06-22 1993-01-12 Adir Et Compagnie Chalcones
US20050250772A1 (en) * 2000-04-13 2005-11-10 Shelby Nancy J Methods for inducing anti-anxiety and calming effects in animals and humans
US20060166981A1 (en) * 2000-04-13 2006-07-27 Rosenfeld Mark J Novel compounds for use in weight loss and appetite suppression in humans
US7521467B2 (en) 2000-04-13 2009-04-21 Seroctin Research & Technology, Inc. Compounds for use in weight loss and appetite suppression in humans
US7541356B2 (en) 2000-04-13 2009-06-02 Seroctin Research & Technology, Inc. Compounds for use in weight loss and appetite suppression in humans
US7794761B2 (en) 2000-04-13 2010-09-14 Seroctin Research & Technology, Inc. Methods for inducing anti-anxiety and calming effects in animals and humans
US7507731B2 (en) 2003-11-20 2009-03-24 Seroctin Research & Technology, Inc. Compounds for use in weight loss and appetite suppression in humans
US7521468B2 (en) 2003-11-20 2009-04-21 Seroctin Research & Technology, Inc. Compounds for use in weight loss and appetite suppression in humans
US7524877B2 (en) 2003-11-20 2009-04-28 Seroctin Research & Technology, Inc. Compounds for use in weight loss and appetite suppression in humans
RU2788047C1 (ru) * 2021-12-30 2023-01-16 федеральное государственное автономное образовательное учреждение высшего образования "Пермский национальный исследовательский политехнический университет" Седативное средство на основе 3-(2-(4-фторофенил)-2-оксоэтилиден)-3,4-дигидро-2н-бензо[b][1,4]оксазин-2-она

Also Published As

Publication number Publication date
FR2588868A1 (fr) 1987-04-24
DK504986D0 (da) 1986-10-21
PT83593B (pt) 1989-05-31
DK504986A (da) 1987-04-22
JPS62126180A (ja) 1987-06-08
FR2588868B1 (fr) 1988-11-10
PT83593A (fr) 1986-11-01
EP0223674A1 (fr) 1987-05-27

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